(a) Field of the Invention
This invention relates to 5-(lower-alkyl)-1,6-naphthyridin-2(1H)-ones, their cardiotonic use and their preparation.
(b) Description of the Prior Art
Chemical Abstracts 72, 12,615d (1970) is reproduced as follows: "Chemotherapeutics. IV. 1,6-Naphthyridine N-oxides. Takahashi Torizo; Hamada Yoshiki; Takeuchi Isao; Uchiyama Hideko (Fac. Pharm., Meijo Univ., Nagoya, Japan). Yakugaku Zasshi 1969, 89(9), 1260-5 (Japan). Various reaction conditions were examd. for the formulation of I, II, III, and IV by the application of hydrogen peroxide to 1,6-naphthyridine in HOAc soln. ##STR1## Ir, uv, NMR, and mass spectra of these four compds. were measured to detect their structure, which was detd. by chem. methods such as redn. with Raney Ni. Antibacterial action of I, II, and III was examd."
2-Hydroxy-3-methyl-1,6-naphthyridine, the tautomeric form of 3-methyl-1,6-naphthyridin-2(1H)-one, was reportedly prepared by Ogata et al. [Chem. Pharm. Bull. 20, 2264 (1972)] in two steps by first photocyclization of N-(4-pyridinyl)methacrylamide to produce 1,2,3,4-tetrahydro-3-methyl-2-oxo-1,6-naphthyridine and then dehydrogenating said tetrahydro compound by heating it in acetic acid. 3-Cyano-2-hydroxy-1,6-naphthyridine, the tautomeric form of 3-cyano-1,6-naphthyridin-2(1H)-one, was reportedly prepared by Hawes et al [J. Med. Chem. 16, 849 (1973)] by refluxing 4-aminonicotinaldehyde and ethyl cyanoacetate in ethanol in the presence of piperidine. The compound was reportedly used as an intermediate for preparing 2-amino-3-cyano-1,6-naphthyridine, a "potential diuretic agent", and is shown as having low diuretic activity.
In another paper Hawes et al [J. Heterocycl. Chem. 11, 151 (1974)] show the preparations of: (a) 3-cyano-1,6-naphthyridin-2(1H)-one by reacting 4-aminonicotinaldehyde with N,N-dimethylcyanoacetamide or 4-cyanoacetylmorpholine in the presence of piperidine; (b) 3-carbamyl-1,6-naphthyridin-2(1H)-one by using malonamide in place of N,N-dimethylcyanoacetamide as in (a); and, (c) 3-carboethoxy-1,6-naphthyridin-2(1H)-one by using diethyl malonate instead of malonamide as in (b).
Moller et al [Ann. 612, 153 (1957)] show as intermediates the 3-R-4-OH-1,6-naphthyridines where R is H, NH.sub.2 and COOH.